Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Outcomes of pre-operative brachytherapy followed by hysterectomy for early cervical cancer.

OBJECTIVE: The standard of care for early cervical cancer is radical hysterectomy; however, consideration of pre-operative brachytherapy has been explored. We report our experience using pre-operative brachytherapy plus Wertheim-type hysterectomy to treat early stage cervical cancer. METHODS: This single-center study evaluated consecutive patients with histologically proven node-negative early stage cervical cancer (International Federation of Gynecology and Obstetrics 2009 stage IB1-IIB) that was treated using pre-operative brachytherapy and hysterectomy. Pre-brachytherapy staging was performed using magnetic resonance imaging (MRI) and pelvic lymph node assessment was performed using lymphadenectomy. The tumor and cervical tissues were treated using brachytherapy (total dose 60 Gy) followed by Wertheim-type hysterectomy. The study included patients from January 2000 to December 2013. RESULTS: A total of 80 patients completed a median follow-up of 6.7 years (range 5.4-8.5). The surgical specimens revealed a pathological complete response for 61 patients (76%). Patients with incomplete responses generally had less than 1 cm residual tumor at the cervix, and only one patient had lymphovascular space involvement. The estimated 5-year rates were 88% for overall survival (95% CI 78% to 94%) and 82% for disease-free survival (95% CI 71% to 89%). Toxicities were generally mild-to-moderate, including 26 cases (33%) of grade 2 late toxicity and 10 cases (13%) of grade 3 late toxicity. Univariate analyses revealed that poor disease-free survival was associated with overweight status (≥25 kg/m2, HR 3.05, 95% CI 1.20 to 7.76, p=0.019) and MRI tumor size >3 cm (HR 3.05, 95% CI 1.23 to 7.51, p=0.016). CONCLUSIONS: Pre-operative brachytherapy followed by Wertheim-type hysterectomy may be safe and effective for early stage cervical cancer, although poorer outcomes were associated with overweight status and MRI tumor size >3 cm.

BioPro-RCMI-1505 trial: multicenter study evaluating the use of a biodegradable balloon for the treatment of intermediate risk prostate cancer by intensity modulated radiotherapy; study protocol.

BACKGROUND: Prospective trials have demonstrated the advantage of dose-escalated radiotherapy for the biochemical and clinical control of intermediate risk prostate cancer. Dose escalation improves outcomes but increases risks of urinary and bowel toxicity. Recently the contribution of "spacers" positioned in the septum between the rectum and the prostate could improve the functional results of intensity modulated radiation therapy (IMRT). To date most of the evaluated devices were polyethylen glycol (PEG) and hyaluronic acid (HA). Men on the Spacer arm had decreased bowel toxicity and less decline in both urinary and bowel quality of life as compared to Control men in a randomized trial. METHODS: This is an interventional, multi-center study to evaluate the use of biodegradable inflatable balloon for patients with intermediate risk prostate cancer treated by IMRT (74 to 80 Gy, 2 Gy/fraction) with daily image guided radiotherapy. DISCUSSION: This multicenter prospective study will yield new data regarding dosimetric gain and implantation stages of Bioprotect balloon. Acute and late toxicities and quality of life will be registered too. TRIAL REGISTRATION: NCT02478112 , date of registration: 15/06/2015.

Survey of current practices from the International Stereotactic Body Radiotherapy Consortium (ISBRTC) for head and neck cancers.

AIM: To provide a multi-institutional description of current practices of stereotactic body radiotherapy (SBRT) for head and neck cancer. MATERIALS & METHODS: 15 international institutions with significant experience in head and neck SBRT were asked to complete a questionnaire covering clinical and technical factors. RESULTS: SBRT is used 10-100% of the time for recurrent primary head and neck cancer, and 0-10% of the time in newly diagnosed disease. Five centers use a constraint for primary disease of 3-5 cm and 25-30 cc. Nine institutions apply a clinical target volume expansion of 1-10 mm and 14 use a planning target volume margin of 1-5 mm. Fractionation regimens vary between 15 and 22 Gy in 1 fraction to 30-50 Gy in 5 or 6 fractions. The risk of carotid blowout quoted in the re-irradiation setting ranges from 3 to 20%. CONCLUSION: There is considerable heterogeneity in patient selection and techniques in head and neck SBRT practice among experienced centers.

Surface imaging, laser positioning or volumetric imaging for breast cancer with nodal involvement treated by helical TomoTherapy.

A surface imaging system, Catalyst (C-Rad), was compared with laser-based positioning and daily mega voltage computed tomography (MVCT) setup for breast patients with nodal involvement treated by helical TomoTherapy. Catalyst-based positioning performed better than laser-based positioning. The respective modalities resulted in a standard deviation (SD), 68% confidence interval (CI) of positioning of left-right, craniocaudal, anterior-posterior, roll: 2.4 mm, 2.7 mm, 2.4 mm, 0.9° for Catalyst positioning, and 6.1 mm, 3.8 mm, 4.9 mm, 1.1° for laser-based positioning, respectively. MVCT-based precision is a combination of the interoperator variability for MVCT fusion and the patient movement during the time it takes for MVCT and fusion. The MVCT fusion interoperator variability for breast patients was evaluated at one SD left-right, craniocaudal, ant-post, roll as: 1.4 mm, 1.8 mm, 1.3 mm, 1.0°. There was no statistically significant difference between the automatic MVCT registration result and the manual adjustment; the automatic fusion results were within the 95% CI of the mean result of 10 users, except for one specific case where the patient was positioned with large yaw. We found that users add variability to the roll correction as the automatic registration was more consistent. The patient position uncertainty confidence interval was evaluated as 1.9 mm, 2.2 mm, 1.6 mm, 0.9° after 4 min, and 2.3 mm, 2.8 mm, 2.2 mm, 1° after 10 min. The combination of this patient movement with MVCT fusion interoperator variability results in total standard deviations of patient posi-tion when treatment starts 4 or 10 min after initial positioning of, respectively: 2.3 mm, 2.8 mm, 2.0 mm, 1.3° and 2.7 mm, 3.3 mm, 2.6 mm, 1.4°. Surface based positioning arrives at the same precision when taking into account the time required for MVCT imaging and fusion. These results can be used on a patient-per-patient basis to decide which positioning system performs the best after the first 5 fractions and when daily MVCT can be omitted. Ideally, real-time monitoring is required to reduce important intrafraction movement.

Inverse treatment planning for spinal robotic radiosurgery: an international multi-institutional benchmark trial.

Stereotactic radiosurgery (SRS) is the accurate, conformal delivery of high-dose radiation to well-defined targets while minimizing normal structure doses via steep dose gradients. While inverse treatment planning (ITP) with computerized optimization algorithms are routine, many aspects of the planning process remain user-dependent. We performed an international, multi-institutional benchmark trial to study planning variability and to analyze preferable ITP practice for spinal robotic radiosurgery. 10 SRS treatment plans were generated for a complex-shaped spinal metastasis with 21 Gy in 3 fractions and tight constraints for spinal cord (V14Gy < 2 cc, V18Gy < 0.1 cc) and target (coverage > 95%). The resulting plans were rated on a scale from 1 to 4 (excellent-poor) in five categories (constraint compliance, optimization goals, low-dose regions, ITP complexity, and clinical acceptability) by a blinded review panel. Additionally, the plans were mathemati-cally rated based on plan indices (critical structure and target doses, conformity, monitor units, normal tissue complication probability, and treatment time) and compared to the human rankings. The treatment plans and the reviewers' rankings varied substantially among the participating centers. The average mean overall rank was 2.4 (1.2-4.0) and 8/10 plans were rated excellent in at least one category by at least one reviewer. The mathematical rankings agreed with the mean overall human rankings in 9/10 cases pointing toward the possibility for sole mathematical plan quality comparison. The final rankings revealed that a plan with a well-balanced trade-off among all planning objectives was preferred for treatment by most par-ticipants, reviewers, and the mathematical ranking system. Furthermore, this plan was generated with simple planning techniques. Our multi-institutional planning study found wide variability in ITP approaches for spinal robotic radiosurgery. The participants', reviewers', and mathematical match on preferable treatment plans and ITP techniques indicate that agreement on treatment planning and plan quality can be reached for spinal robotic radiosurgery.

Safety of adjuvant intensity-modulated postoperative radiation therapy in endometrial cancer: Clinical data and dosimetric parameters according to the International Commission on Radiation Units (ICRU) 83 report.

AIM: To report a single-institution experience using postoperative pelvic Intensity Modulation Radiation Therapy (IMRT) using tomotherapy accelerators (TA) in postoperative endometrial cancer (EC) regarding ICRU 83 recommendations. BACKGROUND: IMRT in gynecological malignancies provides excellent dosimetric data, lower rates of adverse events and clinical data similar to historical series. MATERIAL AND METHODS: Seventy-six patients with EC were postoperatively treated with adjuvant IMRT using TA. The IMRT dose was 45 Gy for patients without positive lymph nodes and Type I histology and 50.4 Gy for patients with positive lymph nodes and/or type II histology. RESULTS: With a median follow-up of 29 months, the 12- and 24-month Overall Survival (OS) and Disease-Free Survival (DFS) were 96%, 93%, 87%, and 74%, respectively. Age of less than 60 years was associated with better OS (HR: 8.9; CI: 1.1-68) and DFS (HR: 3.5; CI: 1.2-10.2). Patients with Type II and Type I Grade III histology had a worse OS (HR: 3.3; CI: 1.1-11). Five women (6.6%) presented in-field local vaginal recurrence, 2 (2.6%) presented non-in-field vaginal recurrence, 4 (5.2%) presented pelvic node and distant recurrence and 11 (14.4%) presented only distant metastases. One patient stopped radiation treatment due to Grade III acute diarrhea. No Grade III late toxicity was observed. Planning Target Volume (PTV) coverage showed mean D2, D50, D95, and D98 of 51.64-46.23 Gy, 49.49-44.97 Gy, 48.62-43.96 Gy, and 48.47-43.58 Gy for patients who received 45 and 50.4 Gy, respectively. CONCLUSIONS: IMRT with TA in postoperative EC shows excellent conformity and homogeneity of PTV dose. Without Grade III late toxicity, data from this cohort demonstrated the utility of IMRT.

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

A phase II study of cisplatin with intravenous and oral vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy with oral vinorelbine and cisplatin for locally advanced non-small cell lung cancer.

BACKGROUND: Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. METHODS: Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy. RESULTS: Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis. CONCLUSION: In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01839032.

Extreme hypofractionated stereotactic radiotherapy for localized prostate Cancer: Efficacy and late urinary toxicity according to transurethral resection of the prostate history.

Background and purpose: Extreme hypofractionated stereotactic body radiotherapy (SBRT) is a therapeutic alternative for localized low- or intermediate-risk prostate cancer. Despite the availability of several studies, the toxicity profile of SBRT has not been comprehensively described. This real-world evidence study assessed the efficacy and toxicities associated with this regimen, and potential prognosis factors for genitourinary toxicities. Materials and methods: This retrospective study included 141 consecutive patients with localized prostatic adenocarcinoma treated with CyberKnife™ SBRT, as primary irradiation, at the Oscar Lambret Center between 2010 and 2020. The prescribed dose was 36.25 Gy in 5 fractions. Acute and late toxicities were graded according to the CTCAE (version 5.0). Biochemical recurrence-free survival (bRFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The cumulative incidence of biochemical recurrence (cBR) was estimated using the Kalbfleisch-Prentice method. Results: Among the included patients, 13.5 % had a history of transurethral resection of the prostate (TURP). The median follow-up was 48 months. At 5 years, bRFS, cBR, and OS were 72 % (95 %CI: 61-81), 7 % (95 %CI: 3-14), and 82 % (95 %CI: 73-89), respectively. Twenty-nine patients experienced at least one late toxicity of grade ≥ 2; genitourinary (N = 29), including 3 cases of chronic hematuria, and/or gastrointestinal (N = 1). The cumulative incidence of late urinary toxicity of grade ≥ 2 was 20.6 % at 5 years (95 %CI: 13.9-28.1). Multivariate analysis revealed that a history of TURP was significantly associated with late urinary toxicity of grade ≥ 2, after adjusting for clinical target volume (Odds Ratio = 3.06; 95%CI: 1.05-8.86; P = 0.04). Conclusion: Extreme hypofractionated SBRT is effective for localized prostate cancer with a low risk of late toxicity. A history of TURP is associated with a higher risk of late urinary toxicity. These findings may contribute to the optimal management of patients treated with this regimen, particularly those with a history of TURP.

Stereotactic reirradiation in the treatment of head and neck cancers: A retrospective study on the long-term experience of the Oscar Lambret Center.

BACKGROUND AND PURPOSE: Stereotactic radiotherapy potentially treats unresectable recurrences of previously irradiated head and neck (H&N) cancer. This study aimed to assess its efficacy and safety and evaluate prognostic factors. MATERIALS AND METHODS: We conducted a large retrospective series that included 110 patients who had undergone 36-Gy, six-fraction stereotactic reirradiation (CyberKnife®) for recurrent/secondary H&N cancer between 2007 and 2020 at the Oscar Lambret Center. Patient characteristics and toxicities were assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS: Median follow-up time was 106.3 months. The 2-year OS rate was 43.8 % (95 % confidence interval, 95 % CI, 34.3-52.9) and the median survival was 20.8 months (95 % CI, 16.5-26.3). The cumulative 2-year local-recurrence, regional-recurrence, and distant-metastasis rates were 52.2 % (95 % CI, 42.4-61.1 %), 12.8 % (95 % CI, 7.4-19.8 %), and 11 % (95 % CI, 6.0-17.6 %), respectively. 73 patients received concomitant cetuximab, and it was not significantly beneficial (HR = 1.34; 95 % CI, 0.80-2.26; p = 0.26). The cumulative incidences of grade ≥ 2 late toxicity was 42 % (CI95%: 33-51) at 24 months. Two grade 4 bleedings and no treatment-related deaths were reported. CONCLUSION: In a large retrospective series of SBRT reirradiation for recurrent or second primary H&N cancers, we observed a median OS of 20.8 months, with a cumulative incidence of grade ≥ 2 late toxicity of 42 % at 24 months. Such a treatment is feasible. However, local recurrence rates remain non-negligible, warranting further research. Radiosensitizer use is currently under study. Therefore, establishing a balance between therapeutic modifications and toxicity is essential.

Interstitial needles versus intracavitary applicators only for locally advanced cervical cancer: results from real-life dosimetric comparisons.

Background and purpose: Image-guided adapted brachytherapy (IGABT) is superior to other radiotherapy techniques in the treatment of locally advanced cervical cancer (LACC). We aimed to investigate the benefit of interstitial needles (IN) for a combined intracavitary/interstitial (IC/IS) approach using IGABT over the intracavitary approach (IC) alone in patients with LACC after concomitant external beam radiotherapy (EBRT) and chemotherapy. Materials and methods: We included consecutive patients with LACC who were treated with IC/IS IGABT after radiochemotherapy (RCT) in our retrospective, observational study. Dosimetric gain and sparing of organs at risk (OAR) were investigated by comparing the IC/IS IGABT plan with a simulated plan without needle use (IC IGABT plan) and the impact of other clinical factors on the benefit of IC/IS IGABT. Results: Ninety-nine patients were analyzed, with a mean EBRT dose of 45.5 ± 1.7 Gy; 97 patients received concurrent chemotherapy. A significant increase in median D90% High Risk Clinical target volume (HR-CTV) was found for IC/IS (82.8 Gy) vs IC (76.2 Gy) (p < 10-4). A significant decrease of the delivered dose for all OAR was found for IC/IS vs IC for median D2cc to the bladder (77.2 Gy), rectum (68 Gy), sigmoid (53.2 Gy), and small bowel (47 Gy) (all p < 10-4). Conclusion: HR-CTV coverage was higher with IC/IS IGABT than with IC IGABT, with lower doses to the OAR in patients managed for LACC after RCT. Interstitial brachytherapy in the management of LACC after radiotherapy provides better coverage of the target volumes, this could contribute to better local control and improved survival of patients.

Intermediate-risk endometrial cancer treated with adjuvant brachytherapy using single dosimetric planning: long-term outcome and toxicity assessment.

OBJECTIVE: Brachytherapy of the vaginal dome is the recommended adjuvant treatment for intermediate-risk endometrial cancer. This study assessed the results of dosimetric planning of high-dose-rate brachytherapy exclusively in the first treatment session. STUDY DESIGN: This retrospective study included all patients who underwent hysterectomy for endometrial cancer followed by adjuvant brachytherapy of the vaginal dome between 2012 and 2015. Local recurrence rates, overall survival (OS) rates, recurrence-free survival (RFS) rates, and related acute and late toxicity rates were evaluated. RESULTS: This analysis included 250 patients, of whom 208 were considered to be at high-intermediate risk of disease recurrence. After a median follow-up of 56 months, the cumulative incidence of local recurrence was 4.8% at 3 years [95% confidence interval (CI) 2.8-8.3] and 7.8% at 5 years (95% CI 4.8-12.6). The 5-year OS rate was 86.2% (95% CI 80.6-90.3), and the 5-year RFS rate was 77.5% (95% CI 71.1-82.7). Acute toxicity occurred in 20 (8%) patients, of which two patients had grade ≥3 toxicity. Only one patient (0.4%) presented with late grade ≥3 toxicity. CONCLUSION: These findings confirm the tolerability of this brachytherapy approach, indicating minimal cases of late grade ≥3 toxicity, associated with a good 5-year OS rate. With the advent of molecular prognostic factors, the current focus revolves around discerning those individuals who gain the greatest benefit from adjuvant therapy, and tailoring treatment more effectively.

Cilengitide targets pediatric glioma and neuroblastoma cells through cell detachment and anoikis induction.

The prognosis of children with high-grade glioma or high-risk neuroblastoma remains poor. Cilengitide is a selective antagonist of αvß3 and αvß5 integrins, which are involved in tumor growth and development of metastasis. We have evaluated the effects of cilengitide on pediatric glioma and neuroblastoma cell lines for the first time. Expression levels of αvß3 and αvß5 were determined by flow cytometry in three neuroblastoma and five pediatric glioma cell lines compared with adult U87-MG before and after irradiation. Cell detachment, cytotoxicity, and cell growth under nonadhesive conditions were measured using the MTS assay. Cell death and apoptosis were assessed by annexin-V/propidium iodide staining. The varying αvß3 and αvß5 expression levels were unrelated to tumor grade. Irrespective of the αvß5 expression level, the pediatric cells expressing αvß3 were dose dependently sensitive to cilengitide. UW479 cells expressed only αvß5 integrin and were not sensitive to cilengitide, suggesting that cilengitide's action largely depends on αvß3 inhibition. Cell detachment resulted in a higher cytotoxicity in pediatric glioma compared with U87-MG cells, which seem able to grow despite the significant cilengitide-induced cell detachment. Growth kinetics on polyHEMA showed that only pediatric glioma cells were sensitive to anoikis and so died after cilengitide-induced detachment. Furthermore, irradiation of glioma cells increased αvß3 expression slightly but not cilengitide sensitivity. Cilengitide's action on glioma and neuroblastoma cells appears to be dependent on αvß3 expression and sensitivity to anoikis. Cilengitide is able to target pediatric glioma and neuroblastoma cells in vitro directly and efficiently. Tumor context could validate these promising observations.

SHARE: a French multicenter phase III trial comparing accelerated partial irradiation versus standard or hypofractionated whole breast irradiation in breast cancer patients at low risk of local recurrence.

The standard treatment for breast cancer patients at low risk of recurrence is based on conservative surgery followed by radiation therapy delivered to the whole breast. The accelerated partial breast irradiation (APBI) concept, developed more than 15 years ago, could be an option in selected patients. However, the ideal patient profile for APBI is still not clearly identified. Recent reports from the American Society for Radiation Oncology (ASTRO) and the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) have suggested selection criteria for "suitable patients" who could receive APBI outside of clinical trials. Currently, there are 6 ongoing phase III trials. All are characterized by a significant heterogeneity regarding inclusion criteria and stratification factors. The French UNICANCER trial (SHARE; ClinicalTrials.gov identifier NCT01247233) will randomize 2,800 patients in 3 arms: APBI (1 week) using 3-dimensional (3D) conformal radiotherapy, standard radiotherapy (6.5 weeks), and hypofractionated radiotherapy (3 weeks). In this article, we review the reported retrospective studies as well as older randomized trials. We will also describe the differences between the 6 ongoing phase III trials and the particularities of the French SHARE trial.

IMRT in the treatment of locally advanced or inoperable NSCLC in the pre-durvalumab era: clinical outcomes and pattern of relapses, experience from the Oscar Lambret Center.

Background: Intensity-modulated conformal radiotherapy (IMRT) has become the technique of choice for the treatment of locally advanced or inoperable non-small cell lung cancer (NSCLC). Nevertheless, this technique presents dosimetric uncertainties, particularly in treating moving targets such as pulmonary neoplasms. Moreover, it theoretically increases the risk of isolated nodal failure (INF) due to reduced incidental irradiation. Objective: The objective of this study was to evaluate the efficacy and safety of IMRT in patients with inoperable NSCLC and to describe the pattern of relapses. Methods: Patients with locally advanced NSCLC treated with radiotherapy and chemotherapy between 2015 and 2018 at the Oscar Lambret Center were retrospectively included in the study. Overall and progression-free survival were estimated using the Kaplan-Meier method. The cumulative incidence of the different components of relapse was estimated using the Kalbfleisch and Prentice method. Prognostic factors for relapse/death were investigated using the Cox model. A comparison with literature data was performed using a one-sample log-rank test. Results: Seventy patients were included, and 65 patients (93%) had stage III disease. All the patients received chemotherapy, most frequently with cisplatin and navelbine. The dose received was 66 Gy administered in 33 fractions. The median follow-up and survival were 49.1 and 39.1 months, respectively. A total of 35 deaths and 43 relapses, including 29 with metastatic components, were reported. The overall survival rates at 1 and 2 years were 80.2% (95% confidence interval 68.3%-88.0%) and 67.2% (95% confidence interval 54.2%-77.3%), respectively. Locoregional relapse was observed in 14 patients, including two INF, one of which was located in the lymph node area adjacent to the clinical target volume. Median relapse-free survival was 15.2 months. No variable was statistically associated with the risk of relapse/death in multivariate analysis. Seven patients (10%) experienced grade 3 or higher toxicity. Conclusion: The use of IMRT for locally advanced or inoperable NSCLC led to favorable long-term clinical outcomes. The rate of locoregional relapse, particularly isolated lymph node failure, was low and comparable with that of the three-dimensional radiotherapy series, as was the rate of early and late toxicities.

A Multicenter Phase 2 Study of Ultrahypofractionated Stereotactic Boost After External Beam Radiotherapy in Intermediate-risk Prostate Carcinoma: A Very Long-term Analysis of the CKNO-PRO Trial.

Background: Genitourinary (GU) or gastrointestinal (GI) complications and tumor relapse can occur in the long term after radiotherapy for prostate cancer. Objective: To assess the late tolerance and relapse-free survival (RFS) in patients undergoing hypofractionated stereotactic boost therapy after external beam radiotherapy (EBRT) for intermediate-risk prostate cancer. Design setting and participants: Seventy-six patients with intermediate-risk prostate carcinoma between August 2010 and April 2013 were included. The first course delivered a dose of 46 Gy by conventional fractionation; the second course was a boost of 18 Gy (3 × 6 Gy) within 10 d. Outcome measurements and statistical analysis: GU and GI toxicities were evaluated as the primary outcomes. The secondary outcomes were overall survival and RFS. The cumulative incidence of toxicity was calculated using a competing-risk approach. Overall survival and RFS were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up period was 88 mo (range, 81-99 mo). Sixty (79%) patients were treated with the CyberKnife and 16 (21%) using a linear accelerator. The cumulative incidences of GU and GI grade ≥2 toxicities at 120 mo were 1.4% (95% confidence interval [CI]: 0.1-6.6%) and 11.0% (95% CI: 5.1-19.4%), respectively. The overall survival and RFS rates at 8 yr were 89.1% (95% CI: 77-95%) and 76.9% (95% CI: 63.1-86.1), respectively. Conclusions: A very long follow-up showed low GU and GI toxicities after a hypofractionated stereotactic boost after EBRT for intermediate-risk prostate cancer. Dose escalation of the boost delivered by hypofractionated radiation therapy appears safe for use in future trials. Patient summary: We found low toxicity and good survival rates after a short and high-precision boost after external beam radiotherapy for intermediate-risk prostate cancer, with a long-term follow-up of 88 mo. This long-term treatment is safe and should be considered in future trials.

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy.

Stereotactic body radiation therapy (SBRT) has made the hypofractionation of high doses delivered in a few sessions more acceptable. While the benefits of hypofractionated SBRT have been attributed to additional vascular, immune effects, or specific cell deaths, a radiobiological and mechanistic model is still needed. By considering each session of SBRT, the dose is divided into hundreds of minibeams delivering some fractions of Gy. In such a dose range, the hypersensitivity to low dose (HRS) phenomenon can occur. HRS produces a biological effect equivalent to that produced by a dose 5-to-10 times higher. To examine whether HRS could contribute to enhancing radiation effects under SBRT conditions, we exposed tumor cells of different HRS statuses to SBRT. Four human HRS-positive and two HRS-negative tumor cell lines were exposed to different dose delivery modes: a single dose of 0.2 Gy, 2 Gy, 10 × 0.2 Gy, and a single dose of 2 Gy using a non-coplanar isocentric minibeams irradiation mode were delivered. Anti-γH2AX immunofluorescence, assessing DNA double-strand breaks (DSB), was applied. In the HRS-positive cells, the DSB produced by 10 × 0.2 Gy and 2 Gy, delivered by tens of minibeams, appeared to be more severe, and they provided more highly damaged cells than in the HRS-negative cells, suggesting that more severe DSB are induced in the "SBRT modes" conditions when HRS occurs in tumor. Each SBRT session can be viewed as hyperfractionated dose delivery by means of hundreds of low dose minibeams. Under current SBRT conditions (i.e., low dose per minibeam and not using ultra-high dose-rate), the response of HRS-positive tumors to SBRT may be enhanced significantly. Interestingly, similar conclusions were reached with HRS-positive and HRS-negative untransformed fibroblast cell lines, suggesting that the HRS phenomenon may also impact the risk of post-RT tissue overreactions.

The Safety and Efficacy of Salvage Stereotactic Radiation Therapy in Patients with Intraprostatic Tumor Recurrence After Previous External Radiation Therapy: Phase 1 Results from the GETUG-AFU 31 Study.

BACKGROUND: There is no consensus on the best local salvage treatment for prostate cancer recurrence after primary external beam radiotherapy. Prospective data on stereotactic body radiation therapy (SBRT) are very scarce. OBJECTIVE: To determine the optimal dose regimen for salvage SBRT. DESIGN, SETTING, AND PARTICIPANTS: The present report concerns the phase 1 part of the GETUG-AFU 31 multicenter open-label study. The main inclusion criteria were histologically proven biochemical recurrence, clinical stage T1-T2 upon relapse, multiparametric magnetic resonance imaging data, prostate-specific antigen (PSA) level ≤10 ng/ml prior to salvage SBRT, PSA doubling time >10 mo, and an International Prostate Symptom Score of ≤12. INTERVENTION: Five or six fractions of 6 Gy were delivered using focal SBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Dose-limiting toxicity (DLT) was defined as grade ≥3 gastrointestinal or genitourinary tract toxicity, or any grade 4 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03) occurring in the first 18 wk following treatment initiation. A time-to-event continual reassessment method was used to select the dose regimen. RESULTS AND LIMITATIONS: Twenty-one patients were treated (median [interquartile range] age: 76.8 yr [72.2-80.8]), including 12 at 6 × 6 dose level. No DLT was observed. The acute grade 2 genitourinary tract toxicity rate was 19%. With a median follow-up of 12.3 mo, the estimated cumulative incidence of late grade 2 genitourinary toxicity was 41.2% (95% confidence interval: 18.1-63.1%). No grade >2 genitourinary toxicity and no grade ≥2 gastrointestinal toxicity were reported. All treated patients were alive and relapse free at the last follow-up. CONCLUSIONS: A 6 × 6 Gy dose regimen was selected for our phase 2 study of salvage SBRT. With a short follow-up period, the level of toxicity appears to be acceptable. PATIENT SUMMARY: There is no consensus on the best local treatment for patients with local relapse after radiotherapy for prostate cancer. Prospective data are very scarce. Our early phase trial allowed us to recommend six fractions of 6 Gy using high-precision radiotherapy for further studies.

Economic evaluation and budget-impact of accelerated partial breast irradiation (APBI) versus standard or hypofractionated whole breast irradiation (WBI) in postmenopausal women with early-stage breast cancer. Results from the French SHARE randomized trial.

PURPOSE: This economic evaluation reports the incremental cost-utility ratio and national budget impact in France of accelerated partial breast irradiation (APBI) vs standard or hypofractionated whole breast irradiation (WBI) in breast cancer patients at low risk of local recurrence. MATERIALS AND METHODS: We compared 490 women randomized to the APBI (ten fractions delivered twice daily over one week) with 488 women in the WBI arm (one fraction per day delivered five days per week over three or six weeks). We took the perspective of the French national health insurance with a three-year time horizon. The outcome was quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio was estimated and uncertainty was explored by probabilistic bootstrapping. Transportation and sick leave costs were added in a sensitivity analysis and a national budget impact analysis based on the incidence of breast cancer estimates in France performed. RESULTS: At three years, the average cost per patient was €2,549 (±1,954) in the APBI arm and €4,468 (±1,586) in the WBI arm (p-value < 0.001), radiotherapy was the main driver of the difference between the two arms. No significant difference was found in QALYs. For an average of 60,000 new cases of breast cancer diagnosed annually in France, 28,000 would be eligible for treatment with APBI. A 100% uptake of APBI would result in a yearly30 million€ cost saving. CONCLUSION: APBI for the treatment of postmenopausal women with early-stage breast cancer is cost saving, with no difference in outcome measured by QALYs.